2 SUSTAINABLE WORM CONTROL STRATEGIES FOR SHEEP A Technical Manual for Veterinary Surgeons and Advisers Dr K.A. Abbott, Royal Veterinary College, London Prof M.A. Taylor, Central Science Laboratory, Sand Hutton, York L.A. Stubbings, LSSC Ltd. Copyright 2004, K.A. Abbott, M.A. Taylor and L.A. Stubbings All rights reserved. No part of this book may be reproduced, stored in a retrieval system or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, except for private use, without the permission of the publishers. ISBN Published by: SCOPS March, 2004 Printed by: Context Publications SCOPS (Sustainable Control of Parasites in Sheep) is directed by a steering committee chaired by the National Sheep Association and including representatives from SNFU, NOAH, AHDA, RUMA, CSL/VLA, SVS, Defra and SAC. The group has been formed to develop strategies for parasite control in sheep and to oversee the delivery of recommendations to the industry.

3 Foreword Gastrointestinal helminths impair the performance of grazing ruminants, reducing voluntary food intake and the efficiency of feed utilisation. Sub-clinical helminth disease can lower the quality of the carcass and reduce milk and wool production During the 1950s and early 1960s considerable research on the epidemiology of gastrointestinal nematodes led to the development of more rational control strategies. This involved the creation of safe pasture for grazing sheep using combinations of arable crops/new leys, grazing with cattle, or mature, less susceptible sheep. Unfortunately, these grazing systems put severe constraints on the use of land, lacked flexibility and often required considerable forward planning. Also the systems were not easily applied to set-stocked sheep on permanent grass. The advent of the first highly effective broad-spectrum anthelmintic, thiabendazole, in 1961 radically changed the approach to control of gastrointestinal parasitism. Frequent treatments, initially with thiabendazole, and more recently with other more effective broad-spectrum anthelmintics have provided an easy and relatively cheap option to control worms and maintain an acceptable level of performance under parasite challenge. Strategic dosing, combined, where practicable with grazing management, has been the mainstay of parasite control strategies for the last years but in the early 1980s it became evident that certain nematodes in the UK were developing resistance to the benzimidazole class of drugs. It is only recently that the problem of widespread resistance to the benzimidazoles and to levamisole has been fully appreciated. Fortunately, the newer class of endectocides, the macrocyclic lactones, are still highly effective. It is paramount that their efficacy is maintained, because it is unlikely that any new class of sheep anthelmintic will be licensed in the UK in the foreseeable future. This technical manual on Sustainable Worm Control in Sheep is very timely. It comprises a synthesis of the views of a panel of experts convened to address the current problems, and the strategies discussed should reduce the selection pressure for anthelmintic resistance. Veterinarians and sheep advisors need to encourage farmers to adopt parasite control practices that will maintain the viability of the sheep industry. Their task will not be easy, as many farmers may be reluctant to change their worming programmes when they perceive them to be working satisfactorily. In addition, on farms where a drug resistance problem is not suspected, changing worm control strategies will have a cost with no apparent immediate benefit. The challenge is to effectively promote the new practices so that anthelmintics will remain effective in controlling worm infection in sheep for many years to come. Dr Bob Coop Formerly Head of Parasitology Moredun Research Institute March 2004

4 Contents 1 Introduction The Need for Change Introduction The sheep industry The parasites The anthelmintics The Parasites The important species of nematode in the UK Life cycles of the gastrointestinal nematodes The typical life cycle Important variations on the basic life cycle Nematodirus battus Strongyloides papillosus Bunostomum trigonocephalum Trichuris ovis Epidemiology Hypobiosis or arrested development Disease Caused by Gastrointestinal Nematodes Disease presentations Teladorsagia (Ostertagia) spp Trichostrongylus spp Haemonchus contortus Nematodirus battus Numbers of worms associated with disease Immunity (acquired resistance) to gastrointestinal nematodes Development of immunity Resistance and resilience Immunity and nutrition Peri-parturient relaxation in immunity (PPRI) Breeding for resistance to parasites Anthelmintics Used Against Gastrointestinal Nematodes Broad-spectrum anthelmintics Narrow spectrum anthelmintics Activity against Nematodirus battus Activity against hypobiotic larvae Injectable formulations of MLs Persistent activity of closantel Cestodes (tapeworms) Activity against ectoparasites Anthelmintic Resistance (AR) What is resistance?

5 5.2 The UK situation Side resistance Resistance selection mechanisms Anthelmintic resistant may be inevitable, but can be delayed The size of in-refugia populations Frequency of treatment Re-infection after dosing Anthelmintic dose rates Reversion to susceptibility Rotation of anthelmintics Combinations of anthelmintics Spread of AR between farms The genetic basis for anthelmintic resistance Anthelmintic Resistance New Guidelines Work out a control strategy with your veterinarian or advisor Avoid introducing resistant worms use quarantine treatments Step 1 - Treatment Step 2 - Holding Step 3 - Turnout to dirty pasture Test for AR on your farm Administer anthelmintics effectively Dose at the rate recommended for the heaviest in the group Check the dosing gun Dosing technique Restrict feed before dosing Use anthelmintics only when necessary Dosing of ewes at tupping Dosing of ewes at turn-out Treatment of lambs FEC monitoring to optimise the timing of anthelmintic use Selecting the appropriate anthelmintic Use narrow spectrum anthelmintics where possible Avoid off-target (inadvertent) use in combination products Rotate anthelmintics where appropriate Using anthelmintics with persistent action Preserve susceptible worms on the farm Part-flock treatment Delay the move after the dose Reduce dependence on anthelmintics Use grazing management Use rams that are bred for resistance to worms Liver Fluke Life-cycle Epidemiology Fasciolosis Treatment and control

7 1 Introduction The Need for Change 1.1 Introduction The routine use of highly effective anthelmintics together with grazing management has controlled worms very successfully in the majority of our sheep flocks for the last 30 years. Recently, the prevalence of anthelmintic resistance (AR) in the UK has risen sharply, and an increasing number of flocks are finding that one or more of the chemical groups are no longer effective against some worm species. The strategies currently employed in most flocks are based on a blue-print approach and have the advantage of being easy to plan and record, are relatively cheap and, historically, have been effective. However, some elements of these strategies are highly selective for AR. If we are to slow the progress of AR over the next 5-10 years, we have to revise worming strategies to reduce the selection pressure for AR and change farmer practices and attitudes. Resistance to anthelmintics is not the only reason for change. Much of the research on which existing strategies are based is years old. In that time there have been significant changes in the size and structure of the sheep industry, the epidemiology of the parasites and the products available. As a veterinarian or sheep adviser, you will know that persuading clients to change worming practices will not be an easy task. The first step will be to explain why the changes are necessary in the light of these new factors. 1.2 The sheep industry Since the introduction of the CAP Sheepmeat Regime in 1980, there has been a huge increase in sheep numbers in the UK. Fig.1.1. illustrates how the sheep population has increased, in particular in lowland and upland areas. During the same period, however, the number of cattle and the area of temporary grassland have both declined by 25%. In the lowlands, EU support for arable farming since 1991 has meant that sheep have been pushed almost exclusively onto areas of permanent grassland, where a mono-culture of sheep production prevails. The net effect is that the opportunities for the alternation of sheep, cattle and conservation, and/or the use of new leys, as a means of reducing worm burdens have been significantly reduced. As a result, sheep farmers have become increasingly reliant on the routine use of anthelmintics in worm control programmes. 100 % of Increase in Breeding Ewes Lowland Upland H ill Fig Changes in the UK Sheep Population 4

8 The challenge ahead is to try to balance the need to control worms, safeguarding both animal performance and welfare, with a reduction in the selection pressure for resistance in the worm populations. 1.3 The parasites There have been noticeable changes in the epidemiology of many of the most common sheep endoparasites in recent years. We do not know if this is due to climate change, selection pressures, changes in production systems or indeed a function of them all. However it is clear that our worm control strategies need to take these into account. Examples of the sort of changes that have occurred are: Haemonchus contortus previously described as a problem confined to the South East of England, Haemonchus is now widespread and is frequently found in Scotland. This has profound implications for control strategies, particularly in adult sheep. Nematodirus battus historically seen as a spring problem, N battus is now also seen in the autumn. Trichostrongylus spp causes the black scour traditionally seen in the autumn in store lambs. Now it is frequently encountered earlier in the summer months, causing losses in younger lambs. Conversely in mild winters it causes problems much later than previously described. 1.4 The anthelmintics Since the development of the worming strategies of the 1970s and 80s, the macrocyclic lactone (ML) group has been added to the range of anthelmintics available to sheep farmers. Current research suggests that resistance to the ML group is still relatively rare in the UK. In contrast, the prevalence of resistance to the benzimidazole (BZ) group has increased dramatically between 1991 and 2000 and is now quite high in the UK, (Fig. 1.2.). Reports of LM resistance have also escalated in recent years BZ Resistant Farms % Average 2000 A verage 1991 Lowland Upland Hill Fig Prevalence of BZ Resistance on Farms in Scotland (Moredun 2001) As the prevalence of resistance to the ML group is still rare, we must strive to preserve the activity of this group of chemicals for as long as possible if we are to maintain an acceptable level of worm control in our flocks. 5

9 The situation with respect to the MLs is complicated because they have three distinct advantages for sheep farmers compared with the BZ or LM groups. They are available in injectable preparations as well as oral drenches. They are active against some ecto- as well as endoparasites and offer an alternative to dipping for sheep scab control. One member of the group, moxidectin, has persistent activity against some nematode species. These features have encouraged sheep farmers to use the MLs widely and have lead to an increase in their inadvertent use, for example as an endectocide, when the treatment is being primarily used as an ectoparasiticide. This has implications for the potential development of AR to the MLs. Acting now to minimise the selection pressure for AR to the MLs is the main aim of the new worming guidelines. This manual will help you to devise strategies that utilise anthelmintics when necessary and in a way that targets parasite species more accurately, helping to preserve the activity of the MLs for longer on your clients farms. 6

10 2 The Parasites 2.1 The important species of nematode in the UK There are about 20 different species of nematodes of sheep commonly found in Britain, the most important of which are shown in Table 2.1. The lungworms are included in the table but are not discussed further in this booklet. The liver fluke Fasciola hepatica (a trematode) is discussed in Section 7. Table 2.1. The important nematode parasites of sheep Site Species Features Abomasum Teladorsagia (Ostertagia) circumcincta Small brown stomach worm cm Small intestine Haemonchus contortus Trichostrongylus axei Trichostrongylus colubriformis T vitrinus Nematodirus battus N filicollis N. spathiger Cooperia spp Bunostomum trigononcephalum Strongyloides papillosus Barber s Pole worm cm long and stout. Very obvious to the naked eye. Stomach hair worm cm Black scour worm cm Thin-necked intestinal worm cm Small intestinal worm cm Hookworm cm No common name cm Large intestine Oesophagostomum venulosum Large bowel worm cm Trichuris ovis Chabertia ovina Whipworm 4 8 cm Large-mouthed bowel worm cm Lungs Dictyocaulus filaria Large lungworm Live in bronchi, 3 10 cm Protostrongylus rufescens Muellerius capillaris Live in the small bronchioles cm Small lungworm. Form nodules in lung parenchyma cm 2.2 Life cycles of the gastrointestinal nematodes The typical life cycle The life cycles of the gastrointestinal nematodes (Fig. 2.1.) are all very similar, with one or two minor exceptions, and the following description applies particularly to Teladorsagia, Trichostrongylus and Haemonchus. There is no multiplication within the sheep and the life-cycle is direct i.e. no intermediate host. Adult female worms in the sheep lay eggs that pass out in the faeces and hatch; each egg releasing one first-stage larva (L1). The L1 develop and moult to second stage larvae (L2). The L1 and L2 are active and feed on bacteria in the faeces. At the second moult to the third stage larvae (L3), the cuticle of the L2 remains as a sheath, protecting the L3 but also 7

11 preventing them from feeding. The L3 is the infective stage. L3 migrate on to the herbage where they are ingested by sheep. In the walls of the stomach or intestines they develop into fourth stage larvae (L4), before emerging as adult worms about 14 days later. The prepatent period (between ingestion of L3 and the appearance of eggs in the faeces) is about days. Adult worms that are not expelled from the sheep by immune mechanisms or killed by anthelmintics survive for only a matter of weeks (typically less than 12) before dying naturally. Fig The basic life cycle of the nematode parasites of sheep. 2.3 Important variations on the basic life cycle Nematodirus battus For all Nematodirus spp, development to the L3 takes place within the egg. With N battus, hatching and release of the L3 occurs as a result of climatic stimulus, usually a period of chill followed by a mean day/night temperature of more than 10 o C. The prepatent period can be as short as 14 days Strongyloides papillosus The L3 has no protective sheath. L3 can infect the host by ingestion or by skin penetration. Transmission may also occur to lambs via the milk of the ewe. The prepatent period is about 9 days Bunostomum trigonocephalum Infection of the host occurs by ingestion or through the skin. Following skin penetration the larvae pass to the lungs and then to the small intestine. The prepatent period is about 56 days. 8

12 2.3.4 Trichuris ovis Infection of the host occurs through ingestion of the L1 in the egg. After ingestion the plugs at the ends of the egg are digested and the L1 released. All four moults occur within the sheep. The prepatent period is 1 to 3 months. 2.4 Epidemiology Two terms are used to describe the conditions of pastures containing the free-living nematode stages. Pastures are contaminated if there are eggs and larvae present, but pastures are only infective if there are L3 present and climatic conditions are suitable for them to move onto the herbage where they can be ingested. Both rainfall and temperature influence the infectivity of pastures. The rate of development to the infective stage (L3) is dependent on temperature. Rain tends to increase the infectivity of pastures by assisting in the movement of L3 out of faecal pellets or pats and by providing the film of moisture necessary for L3 to migrate onto herbage. Rainfall records have been used to predict the peak of availability of nematode larvae on pasture, and temperature records are used to predict the risk of nematodirosis in lambs. Development of L3 from eggs deposited in early spring may take weeks but eggs deposited later in the season develop faster. Summer-deposited eggs can give rise to L3 in just 1 2 weeks. Consequently, eggs passed onto pasture in spring and early summer tend to reach the infective stage at about the same time, resulting in high levels of pasture infectivity from mid-summer onwards (Fig. 2.2.). L3 are most active during warm weather and, if they are not ingested, consume their energy stores and suffer high mortality rates. In autumn and winter, L3 can survive longer and some will over-winter on pasture. Some worm species are better at winter survival than others Haemonchus larvae do not survive well in freezing temperatures but Nematodirus eggs can survive prolonged cold temperatures. Pasture larvae Eggs ewes Eggs lambs Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec Fig The epidemiology of nematode parasitism in sheep at pasture Over-wintering L3 provide a source of infection to grazing sheep in late winter and early spring but do not survive long on pasture after ambient temperatures rise. Pasture infectivity tends to decline rapidly to low levels in late April or early May. If spring-lambed ewes are placed on the pasture, contamination with worm eggs occurs first from the ewes themselves (early spring), and then later (late spring and summer) from the lambs as well. In the case of the ewes, the worms producing these eggs have survived over winter in the ewes or have developed from the ingestion of over-wintered L3 in early spring. In the case of the lambs, the worms have arisen from the ingestion of over-wintered L3 then, later in the season, from eggs deposited by the ewes. The source of the high infectivity of pastures in late summer and autumn is the deposition of eggs in spring and early summer. 9

13 This typical pattern (Fig. 2.2.) is seen most clearly in the epidemiology of Teladorsagia and Trichostrongylus. The rise in pasture larval availability in early summer tends to be dominated by Teladorsagia, with Trichostrongylus spp contributing increasingly in late summer and autumn. Haemonchus has a very high biotic potential - each female worm is capable of producing up to 10,000 eggs per day. Warm and wet conditions favour the rapid development of eggs to L3 and pastures can rapidly become highly infective, and can do so at almost any time between mid-spring and late autumn, weather permitting. This proclivity for rapid generation turnover under suitable conditions compensates for the poor over-winter survival of Haemonchus eggs and larvae on pasture. This also means that pastures can change from low Haemonchus infectivity in early spring to high infectivity in summer and autumn. Nematodirus battus has a much slower life-cycle, with infection passed from a lamb crop in one year to the lambs born in the following year. The long survival of Nematodirus eggs permits this relatively long generation interval. As a result of the specific climatic requirements for egg hatching, large numbers of infective larvae can appear on pasture almost synchronously. This usually occurs between April and June each year. When mass hatching coincides with the presence of 6-12 week old lambs, severe outbreaks of nematodirosis can occur (see also Section 3.4). 2.5 Hypobiosis or arrested development The abomasal nematodes Teladorsagia spp, H contortus and T axei are capable of interrupting their development at the L4 stage and persisting for long periods in a state of dormancy or hypobiosis. They then resume their development and become normal, egglaying adults. This interruption of development occurs principally to larvae ingested in the late autumn and winter. It can be considered as an evolutionary adaptation which delays egg production (and death) until the following spring when eggs deposited on pasture have a higher chance of continuing the worm s life-cycle. In the case of ewes, most of the Teladorsagia population in the host between November and February exists as hypobiotic larvae. Between April and September, there are very few, if any, hypobiotic larvae and most parasites exist as adult or actively developing forms. Hypobiosis is important in sheep for two reasons: Resumed development of hypobiotic larvae of Teladorsagia can be responsible for clinical disease in yearling sheep, similar to type II ostertagiosis or winter scours seen in cattle. (See also Section 4.4) The worms arising from hypobiotic larvae in ewes are an important source of pasture contamination in the spring and early summer. Hyperbiosis is the principle way H contortus survives the winter in the UK. The small intestinal parasites, including Nematodirus spp, Trichostrongylus spp and Cooperia spp, are also capable of hypobiosis but this does not appear to be an important feature of their epidemiology. 10

14 3 Disease Caused by Gastrointestinal Nematodes 3.1 Disease presentations Disease caused by gastrointestinal nematodes may be acute in onset, with outbreaks of clinical disease in 10% of a flock or more, and with some mortalities. The devastating effects of such outbreaks on a flock are obvious. Gastrointestinal parasites also cause sub-clinical disease, with reduced growth rate, reduced milk and wool production and reduced body condition. Although far less dramatic, these insidious losses may involve large numbers of sheep for prolonged periods resulting in high costs to the industry. The clinical signs of parasitism caused by the gastrointestinal nematodes fall broadly into two categories. First, signs referable to gastritis and enteritis, typical of infection with Teladorsagia spp, Trichostrongylus spp and Nematodirus spp Second, signs referable to blood loss as a result of infection with Haemonchus contortus. 3.2 Teladorsagia (Ostertagia) spp Confusingly, the sheep nematodes previously referred to as Ostertagia spp have been reclassified as Teladorsagia spp, but they are still widely known by their previous name and the disease they cause, ostertagiosis, has not been renamed! Ostertagiosis is characterised by inappetence, diarrhoea, dehydration, weight loss and death. As a result of the reduced feed intake and dehydration, the sheep appear hollow, with very little rumen-fill. Smaller burdens of parasites may be responsible for poor weight gains in the absence of clinical signs. The poor weight gains are a consequence of reduced appetite, reduced feed intake and losses of plasma protein into the gastro-intestinal tract. Disease results from damage to the abomasal mucosa caused by larvae as they emerge from the gastric glands where they develop, and by the presence of adult worms on the mucosal surface. Ostertagiosis is typically seen in lambs during their first season at grass and usually occurs from mid-summer onwards, associated with the ingestion of relatively large numbers of infective larvae over a short period (type I ostertagiosis). In yearling animals during the winter months, type II ostertagiosis may occur as a result of the synchronous resumption of development of large numbers of hypobiotic larvae that were acquired during the previous autumn grazing. 3.3 Trichostrongylus spp Heavy infections of the small intestinal Trichostrongylus spp (principally T colubriformis and T vitrinus) cause inappetence, diarrhoea, rapid weight loss and death. The common name of the worm (black scour worm) describes the clinical picture. The disease is usually seen in store or replacement lambs during the autumn and winter months but can also occur in lambs from late summer onwards. At lower levels of infection, poor growth rates, sometimes accompanied by soft faeces, are the common signs. Chronic infections of T colubriformis are accompanied by reduced food conversion efficiency (FCE). In the case of the abomasal parasite T axei, diarrhoea, ill-thrift, weight loss and death can occur if large numbers are present. 11

15 3.4 Haemonchus contortus Infections with H contortus are characterised by a regenerative anaemia due to the bloodsucking habits of the worms. Both larval and adult forms of the worm feed on blood and each adult worm is capable of removing about 0.05 ml of blood per day by ingestion and seepage from the lesions. A sheep with 5000 H contortus may lose 250 ml of blood daily. In acute infections, resulting from the ingestion of many infective larvae over a short period of time, animals are weak and are likely to collapse if driven. Pallor of the mucous membranes is striking, but it should be assessed by inspection of the conjunctivae rather than the oral mucosa or skin where differentiation from a normal appearance is difficult. Hyperpnoea and tachycardia are also present. The onset of clinical signs may be so sudden that affected animals are still in good body condition. Acute haemonchosis can be a cause of sudden death. In sub-acute infections, sub-mandibular oedema ( bottle-jaw ) may develop as a result of hypoproteinaemia. Clinically, the condition can resemble fasciolosis (Section 7). Chronic infections are characterised by a more general failure to thrive, with weight loss, poor body condition, sub-mandibular oedema, lethargy and weakness. The chronic nature of the blood loss leads to an exhaustion of iron reserves, and the development of a microcytic anaemia. Diarrhoea is not associated with H contortus infection; in fact affected sheep may be slightly constipated. Haemonchosis can occur in both adults and in young sheep. When lactating ewes are affected there can be a profound depression of milk production leading to lamb deaths and to poorly grown lambs that depend on grazing for survival and then become, themselves, heavily parasitised. 3.5 Nematodirus battus Nematodirosis, due to Nematodirus battus infection, is an example of a parasitic disease where the principal pathogenic effect is attributable to the larval stages. Following ingestion of large numbers of L3 there is disruption of the intestinal mucosa, particularly in the ileum, although the majority of the developing stages are found on the mucosal surface. Development to L4 and then L5 is complete by days from infection and this coincides with severe damage to the villi and erosion of the mucosa leading to villous atrophy. The ability of the intestine to exchange fluids and nutrients is grossly reduced and, with the onset of diarrhoea, the lamb rapidly becomes dehydrated. In severe infections, diarrhoea is the most prominent clinical sign. As dehydration proceeds, the affected lambs become inappetent, diarrhoeic and thirsty, often congregating around drinking troughs. N battus is a major cause of parasitic gastroenteritis in lambs in the spring and on occasions during the autumn. 3.6 Numbers of worms associated with disease If gastrointestinal parasitism is suspected as the cause of an outbreak of disease in a flock, a post-mortem examination and worm count should be performed, preferably on two or three animals. It is not sufficient to attempt to visualise the number of worms in the abomasum or small intestine because, with the exception of H contortus, the worms are difficult to see and counts are impossible. Field techniques for worm counts have been described and are highly recommended. As well as providing an instant diagnosis, they can be used by a veterinarian to demonstrate the parasites to the sheep owner. Immature worms will often be missed, or under-estimated, in field counts but will be detected in worm counts done in laboratories. The numbers of worms present provide definitive evidence to support the diagnosis of parasitic gastroenteritis. In many cases, there are worms of different species present. Although the species vary in pathogenicity, it is acceptable to consider their effects to be additive. 12

16 A points system has been developed as a guide to interpreting worm counts: - Teladorsagia spp Trichostrongylus spp H contortus Nematodirus spp Immature worms 3000 worms = 1 point 4000 worms = 1 point 500 worms = 1 point 4000 worms = 1 point 4000 worms = 1 point A total of two points in a young sheep is likely to be causing measurable losses of productivity although clinical signs and deaths are unlikely unless the total exceeds 3 points. In adult sheep, the thresholds will be correspondingly higher. This system is only intended as a guide. It is important to remember that, for some species, such as N battus, the immature worms are much more pathogenic than the adults. This tray contains a sample (one hundredth) of the abomasal contents of a sheep and over 50 Teladorsagia spp are present in the tray. Each worm is about the size of an eyelash. Staining with iodine before partial clearing of the background has made the worms more visible to the naked eye. One worm is arrowed. Fig Worm counts can easily be done in the field. 3.7 Immunity (acquired resistance) to gastrointestinal nematodes Development of immunity Following exposure to worm parasites, lambs gradually develop immunity against them. The onset of immunity can lead to the expulsion of much of the adult worm burden and the prevention of establishment of most incoming infective larvae. In lambs, this effect is most obvious with N battus infection, where adult parasites are typically expelled 3 4 weeks after the first infection, particularly if the number of infective larvae ingested is high. For most other parasites, immunity develops more gradually, following repeated or continuous ingestion of infective larvae over 2 4 months. Immunity is not 100% effective and small worm burdens persist in immune sheep. If sheep are removed from pasture and kept in a worm-free environment, or dosed with anthelmintics continuously or at high frequency, the immunity wanes and even adult sheep can become highly susceptible again. The small burdens that persist in most adult sheep are important in 13

17 continuing to stimulate the immune system and in maintaining an effective immunity. As well as regulating worm numbers, immune sheep also exert some suppression on the growth and reproductive capacity of the worms in their gastrointestinal tract worms in immune sheep tend to be smaller and to produce fewer eggs than worms in naïve sheep. Lambs start to demonstrate immunity against parasites from 4 5 months of age, the immunity increasing in strength with age and continued exposure to larval challenge. After a full year of grazing, most sheep have a high degree of immunity. High levels of challenge can overwhelm immunity to parasites, particularly during the first year of life Resistance and resilience Resistance to parasites is the ability of sheep to limit the establishment rate, growth, fecundity and survival of worm parasites. Resilience, on the other hand, is the ability of sheep to continue to grow, maintain condition, lactate or reproduce despite being parasitised. We would, of course, like sheep to have both, and in good measure! Most research has been directed at resistance to parasites and ways to enhance it through nutrition and selective breeding (see below). The immunity to parasites we are discussing here concerns the development of resistance, rather than resilience. This resistance is not innate in sheep it is acquired following exposure to parasites. Consequently, the expression of immunity of sheep to worm parasites is often referred to as acquired resistance Immunity and nutrition Feeding high protein feeds can enhance immunity. While there appears to be no effect of nutrition (within limits of reasonable levels of nutrition) on the rate at which immunity develops in young sheep, diets containing feedstuffs high in digestible undegraded protein (e.g., soya bean meal) significantly improve the strength of acquired resistance. This research has not yet been converted into specific recommendations for the use of supplementary feeds as an adjunct to parasite management in sheep, but the general relationship between nutrition and the expression of acquired resistance should be considered when planning worm control strategies Peri-parturient relaxation in immunity (PPRI) There is a relaxation in immunity in adult ewes at about lambing time, which persists for a few weeks of lactation. The consequence of this relaxation is that worms produce more eggs, adult worms are not expelled, a lower proportion of incoming infective larvae are rejected and hypobiotic larvae (of T circumcincta and H contortus) that resume development are also less likely to be expelled. As a result, worm numbers rise and the FEC rises. The PPRI typically commences 2 4 weeks before lambing and persists for 6 8 weeks, after which time ewes recover their immunity. Worm numbers and FECs tend to fall towards their pre-lambing levels. The cessation of lactation brings a rapid return of the ewe s normal immunity. The PPRI is very variable in time of onset and in degree between sheep and between flocks of sheep. Several factors are known to influence it; it is less marked in single-bearing/singlerearing ewes than multiple bearing/rearing ewes and it can be diminished by dietary supplementation with feeds high in undegradable digestible protein (UDP) - see also Fig Breeding for resistance to parasites There are variations between individual sheep within a flock in the strength of their acquired resistance to parasites. Part of this variation is genetic, and it is possible to selectively breed for sheep that are more resistant to internal parasites. In flocks that have undergone selection for low FEC, lambs develop stronger acquired resistance and have lower FECs and lower worm burdens than lambs in unselected flocks. Adult ewes in selected flocks have a smaller rise in FEC during the PPRI and their lambs have lower FECs at weaning. It is important to note that selection affects the strength of acquired resistance. Lambs in selected flocks do not demonstrate any significant advantage over lambs in unselected flocks until they are 4 5 months of age or more. As a tool in worm control, genetic resistance will, therefore, prove to be of the greatest benefit when applied to ewe breeds, rather than terminal sire breeds. A flock of ewes that has been sired by worm-resistant rams will cause less contamination of pastures with worm eggs at all times of the year, including at the time of lambing. This reduction in contamination will provide substantial benefits to their lambs. 14

18 It is also important to recognise that selection for parasite resistance can only be effectively performed in ram-breeding flocks. Even those commercial sheep producers who breed their own ewe-replacements cannot achieve any significant genetic improvement in their flocks by ewe selection if the sires they use to breed ewe replacements come from another flock. If such producers wish to improve the genetic resistance of their flocks they must either breed rams themselves or buy rams from a breeder who has been selecting for resistance to worms. Selection is practised in the UK in about 30 ram-breeding flocks. Until recently, most flocks practising selection were terminal sire breeds (Suffolk, Texel, and Charollais) but, more recently, some breeders of hill-breed rams have started selecting rams for low FEC. This is a trend that should be encouraged by buyers of commercial ewes, such as mules. Breeders interested in learning more about breeding for resistance should contact the Meat and Livestock Commission, or its Signet Breeding Services division. Evidence from selection in Romney sheep in New Zealand indicates that substantial and useful improvement can be made over a 10-year period, with selected flocks requiring substantially fewer anthelmintic treatments. Selection for low FEC does not appear to lead to significant correlated responses in resilience to parasites (as opposed to resistance). Experiments have produced conflicting results about the existence of correlated responses between FEC and production traits such as growth rate. It is clear, though, that if selection for low FEC is pursued as the only or dominant trait, then the opportunity to continue selection for other traits is foregone. Breeders are advised to combine moderate selection pressure for low FEC with continued selection for production traits, such as litter size, maternal ability, growth rate and fat depth. 15

19 4 Anthelmintics Used Against Gastrointestinal Nematodes Sheep anthelmintics have either a broad or narrow spectrum of activity. 4.1 Broad-spectrum anthelmintics The broad spectrum anthelmintics can be divided into three groups on the basis of chemical structure and mode of action (Table 4.1.). These groups are: Group 1 - BZ, Benzimidazole (BZ) ( white drenches). All are effective against nematodes and are ovicidal. Most are efficacious against tapeworms. After administration, the BZ passes into the rumen, which acts as a reservoir, allowing gradual release into the bloodstream. BZs act by inhibiting tubulin activity in intestinal cells of nematodes or tegumental cells of cestodes, preventing uptake of glucose. The longer the time it stays in the animal the more effective it is. There is one BZ anthelmintic (triclabendazole) which is narrow spectrum (liver fluke only) and differs from all the other BZ in many respects but is classed with them because of its chemical structure. Group 2 - LM, Levamisole/morantel (LM) ( yellow drenches) Includes the imidazothiazoles (levamisole) and tetrahydropyrimidines (morantel). These drugs are rapidly absorbed and excreted and most of the dose is lost from the system within 24 hours. Therefore, it is not essential to maintain high concentrations in the sheep for protracted periods. LMs act on the nerve ganglion of the parasite, causing paralysis. They are not ovicidal. The therapeutic index, compared to other anthelmintics, is low. Animals given levamisole may be hyperactive for a few minutes. Toxic signs, due to a stimulant effect on nerve ganglia, may manifest as salivation, bradycardia, and muscular tremors and in extreme cases death from respiratory failure. Injectable levamisole may cause inflammation at the site of injection. Group 3 - AV, Macrocyclic lactones (ML) ( clear drenches) Includes the avermectins (ivermectin/ doramectin) and the milbemycins (moxidectin). These compounds are highly lipophilic and following administration are stored in fat tissue from where they are slowly released. They act on glutamate gated Cl- channels and γ-aminobutyric acid (GABA) neurotransmission sites in nematodes, blocking interneuronal stimulation of inhibitory motor neurones, leading to a flaccid paralysis. 4.2 Narrow spectrum anthelmintics The substituted phenols (nitroxynil) and the salicylanilides (closantel, oxyclozanide) are narrow spectrum anthelmintics. They are effective only against trematodes and blood sucking nematodes (Haemonchus and Fasciola). They act by uncoupling oxidative phosphorylation at the mitochondrial level, reducing the availability of ATP, NADH, NADPH. In the host they bind to plasma protein, which increases the duration of activity against blood sucking parasites. The fasciolicides are discussed further in Section 7. 16

21 Table 4-2. Activity of sheep anthelmintics against lungworms, tapeworm and ectoparasites Activity against Compound Lungworms Tapeworms Ectoparasites Broad-spectrum Benzimidazoles + ± - Levamisole Morantel Macrocyclic lactones + - ± Narrow-spectrum Salicylanilides and substituted phenols - ± ± not licensed for cestode activity in the UK. 4.3 Activity against Nematodirus battus The BZs and levamisole possess high activity against the adult and immature larvae of N battus. The MLs have variable activity against N battus although doramectin at increased dose rate is active against L4 larvae of this species. Moxidectin (oral or injectable) has no persistent activity against N battus. 4.4 Activity against hypobiotic larvae Albendazole, fenbendazole, oxfendazole, netobimin, levamisole, doramectin, ivermectin, and moxidectin are effective against arrested fourth stage larvae of the abomasal parasites. Morantel is ineffective against mucosal or arrested stages. 4.5 Injectable formulations of MLs Ivermectin (IVM), doramectin (DOR) and moxidectin (MOX) are available for sheep either as injectable formulations, or oral drenches (not DOR). Administration by injection leads to better absorption and a longer half-life than oral treatment. Only one product (MOX) has a licensed claim for persistent activity in sheep (although all injectable MLs have persistent activity against some, but not all, worm species). MOX will prevent re-infection with ML-susceptible Teladorsagia spp and H contortus for 5 weeks. The period of protection from re-infection with Trichostrongylus colubriformis is much shorter. 4.6 Persistent activity of closantel Closantel will prevent the establishment of all (susceptible) H contortus larvae for four weeks after dosing and will reduce establishment rates of larvae for at least one further week. 4.7 Cestodes (tapeworms) The BZs are generally effective in controlling tapeworm infections. Praziquantel is a specific treatment for tapeworm infections only, but is currently not registered in the UK. 4.8 Activity against ectoparasites The MLs are also active against sucking lice (Linognathus spp), nasal bot flies (Oestrus) and mange mites (Psoroptes, Sarcoptes, Chorioptes). There is little or no activity against chewing lice (Bovicola ovis) (also called biting lice), ticks or keds. 18

22 5 Anthelmintic Resistance (AR) Resistance to all the main anthelmintic classes has been exhibited by nematode populations in most sheep-rearing countries over the last twenty years. 5.1 What is resistance? Resistance is the heritable ability of the parasite to tolerate a normally effective dose of the anthelmintic. The parasite is considered resistant if it survives exposure to the standard recommended dose of the anthelmintic and the ability to survive is passed on to its offspring. Resistance is best viewed as drug tolerance, since resistant individuals can often be removed by exposure to higher dose rates of anthelmintic up to the maximum tolerated dose. We measure degrees of anthelmintic resistance in a number of ways including field tests like faecal egg count reduction trials (FECRTs) and laboratory assays, like the larval development test (LDT)(see Section 8). In FECRTs we expect an effective anthelmintic to reduce egg counts by 100%, ie, to zero. When measured this way, resistance is said to exist if the reduction in egg count is less than 95% (point B in Fig. 5.1.) Anthelmintics will continue to give clinical responses in parasitised sheep even if the reduction in faecal egg count (FEC) is substantially less than 95%. Consequently, sheep farmers may not be aware that resistance to an anthelmintic is present if they are still achieving 80%-90% reduction in FEC (point C in Fig 5.1.). At this level, however, significant production penalties from poor worm control may be incurred and, additionally, resistance is expected to become more severe quite rapidly if the anthelmintic remains in use. Resistant alleles Homozygous resistant worms 1.0 Frequency A B C 0.0 Time Fig 5.1. The rate at which AR appears in a flock Point A, resistance alleles are at very low levels; B, resistance detectable in tests; C, resistance apparent as a clinical problem. Anthelmintic resistance is not the only reason that anthelmintics sometimes appear to fail to control worm parasites. Other reasons include: Dosing with insufficient anthelmintic due to: underestimation of the animal's weight poorly maintained dosing equipment 19

23 Failure to follow the manufacturer's instructions: not storing the products correctly using products beyond their use-by date mixing anthelmintics with other products Rapid re-infection of animals after treatment from highly infective pastures Use of the incorrect drug for the target worms 5.2 The UK situation In the UK, anthelmintic resistance has been confirmed in a number of species of sheep nematodes. Benzimidazole resistance has been reported in Teladorsagia (Ostertagia) circumcincta, Haemonchus contortus, Cooperia curticei and Trichostrongylus spp. Levamisole resistance has been reported in T circumcincta, C curticei and Trichostrongylus spp. Evidence of ML resistance has been reported in T circumcincta in sheep flocks and a goat flock. In each of the flocks with ML resistance, there were also BZ and LM resistant parasites on the same farm. Based on surveys conducted in Scotland and England since 2000, a large proportion of lowland farms has BZ resistance and a smaller, but a significant proportion has LM resistance. The prevalence amongst hill farms may be lower than lowland farms. ML resistance is probably still at a low level, but its rapid emergence in other sheep-rearing countries highlights the importance of exercising some control over its development and spread between flocks, before it becomes widespread in the UK. 5.3 Side resistance Anthelmintics within the same class share the same mode of action. When resistance appears to one anthelmintic in a class, other anthelmintics in the same class will also be affected. Thus worms that are resistant to, for example, oxfendazole, are also resistant to other BZ anthelmintics, such as fenbendazole, ricobendazole and albendazole. Worms that are resistant to ivermectin will also show side-resistance to doramectin and moxidectin, although moxidectin usually demonstrates higher efficacy against ML-resistant parasites than ivermectin. 5.4 Resistance selection mechanisms Anthelmintic resistant may be inevitable, but can be delayed The genes, or alleles, which allow parasites to be resistant to anthelmintics are believed to be in existence in unselected worm populations (see the text box on page 24 for a detailed description). Consequently, for all anthelmintics that have been invented to date, it appears that the development of AR is an inevitable consequence of their use but its development can be delayed. There are several factors that have been shown to influence the rate at which AR appears in a worm population, and they are discussed below. It is our improved understanding of these factors that has led to the development of new guidelines for anthelmintic use, which are discussed in Section The size of in-refugia populations In any parasite ecosystem, there are two sub-populations of worms; the parasitic and the free-living. It is only the parasitic sub-population (the parasites within the host) that can be exposed to any anthelmintic treatment. Worms that are in the free-living sub-population (eggs, L1, L2, L3 - see Section 2) are not exposed to the anthelmintic and are said to be in refugia 20

24 (Fig 5.2.). Any worms in sheep that are not treated also contribute to the in refugia subpopulation. One of the important factors influencing the rate at which resistance develops in a worm population is the relative size of the exposed population and the unexposed or in refugia population. In general, the larger the in refugia population in comparison to the exposed population, the more slowly resistance will develop. Fig 5.2. The exposed and in refugia worm populations The worms inside the dosed sheep are exposed to the anthelmintic. Worms that are free-living on pasture, or are adults or immatures in untreated sheep are in refugia. The in refugia population is typically 100 to 10,000 times larger than the exposed population and the relative sizes of these two populations influences how rapidly AR develops. There are resistant and susceptible worms in both populations but only the susceptible worms in the exposed population (in blue) are removed by treatment Frequency of treatment The more frequently treatment is given, the faster AR develops. The underlying principle of selection for AR is that treatment gives the resistant worms a reproductive advantage over the susceptible worms. For two to three weeks or so after dosing, before newly ingested L3 have become egg-laying adults, the only eggs being passed in the faeces of dosed sheep are from worms which survived treatment. When the interval between dosing becomes shorter, and approaches the pre-patent period of the worm, the susceptible worms have less and less opportunity to produce eggs and most, or all, pasture contamination occurs with eggs from resistant parasites. If this strategy is continued the susceptible population is progressively replaced with a resistant one. Frequency of dosing does not exert its effect on AR development in isolation from other factors that contribute to AR. For example, if the in refugia population is small, replacement happens faster and AR may appear after relatively few treatments. Modeling studies have suggested that a strategy of two treatments, combined each time with a move to lowcontamination pasture, selects for resistance as rapidly as five treatments without using lowcontamination pasture. The lessons from these studies are that not all high-frequency dosing 21

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